The Role of the Dorsolateral Prefrontal Cortex in Ego Dissolution and Emotional Arousal During the Psychedelic State

Psychedelics such as LSD are being revisited for their therapeutic potential in mood and anxiety disorders, and prior clinical work suggests substantial acute psycho-emotional effects that may relate to treatment outcomes. The dorsolateral prefrontal cortex (DLPFC) is implicated in mood regulation and shows hemispheric specialisation in interventions such as transcranial magnetic stimulation (TMS): excitation of the left DLPFC is linked to antidepressant effects, whereas modulation of the right DLPFC is associated with changes in arousal and mania-like states. Ego dissolution and emotional arousal are two prominent dimensions of the psychedelic experience; both can be affectively positive or anxiety-inducing and overlap phenomenologically with aspects of psychosis and mania. Coleman and colleagues set out to test whether the left and right DLPFC play distinct roles in the subjective effects of LSD. Using existing multimodal data from a within-subject, placebo-controlled study, they correlated resting-state functional connectivity (RSFC) of left, right and combined DLPFC seeds (fMRI) with post-scan subjective ratings of ego dissolution, emotional arousal and positive mood, and then examined directed connectivity among the implicated regions using source-localised MEG and Granger causality (GC). The study aimed to map undirected and directed network changes that underlie ego dissolution and emotional arousal under LSD and to probe hemispheric lateralisation within the DLPFC.

Participants were healthy volunteers who each underwent two scanning sessions in randomized order: one with placebo and one with 75 μg intravenous LSD, with sessions separated by at least 14 days. Of 20 participants enrolled, 15 (four females; mean age 30.5 ± 8.0 years) were included in the analysed dataset; one withdrew for anxiety and four were excluded for excessive head motion. Eyes-closed resting-state fMRI and MEG were acquired during the acute drug state: fMRI scans took place after a 60-minute acclimatisation and MEG at 165 minutes post-administration. Subjective data comprised a post-scan Visual Analogue Scale (VAS) with domains including Emotional Arousal, Positive Mood and Ego Dissolution, plus the 11-dimension Altered States of Consciousness (ASC) administered at session end. Functional MRI was acquired on a 3 T scanner with two BOLD resting-state runs of 7:20 min each. Preprocessing used a multi-tool pipeline (FSL, AFNI, FreeSurfer, ANTS) including motion correction, scrubbing (volumes with framewise head displacement > 0.5 mm removed; participants excluded if > 15% volumes scrubbed), spatial smoothing, band-pass filtering, detrending and regression of nine nuisance regressors (six motion, three anatomical). Seed-based RSFC analyses used novel left and right DLPFC seeds derived from an rTMS target coordinate; the left seed was shifted inward to avoid edge artefacts and the right seed mirrored. Seed-to-voxel connectivity was computed for left, right and combined DLPFC seeds, with the opposing hemisphere's seed regressed out in single-hemisphere analyses. Primary analyses compared LSD versus placebo (Delta) and tested correlations between seed connectivity and VAS ratings (Covariate), using FSL-Randomise with 5000 permutations and threshold-free cluster enhancement, reporting clusters at p FWE < 0.05. To assess robustness, a confirmational "reverse" analysis used binarised output clusters from the original covariate analyses as new seeds; the expectation was that this would return clusters within the DLPFC if the original findings were specific. MEG data were acquired on a CTF 275-gradiometer system (600 Hz, two ~7-minute eyes-closed runs; one run randomly selected per subject). Preprocessing in FieldTrip included high-pass filtering, downsampling, epoching into 2-s segments, line-noise removal, artifact rejection (manual and semi-automatic), ICA for ECG/EOG removal, and beamformer source reconstruction. Templates of centroids from the fMRI-derived networks were inversely warped to subject space, and LCMV beamforming was used to extract source time series. Directed connectivity was estimated with Granger causality (GC) using linear autoregressive (AR) models transformed to innovations-form state-space representations; model order selection used the Hannan-Quinn criterion and parameters were estimated by ordinary least squares. Pairwise-conditional GC (conditioning on the other network nodes) was computed in time domain and frequency domain, with frequency-domain GC integrated to obtain band-limited GC in theta, alpha, beta and low-gamma bands (delta and high-gamma were excluded for technical reasons). Statistical inference within conditions used F-tests for time-domain GC and permutation testing (500 epoch-wise permutations) for band-limited GC; between-condition comparisons used Wilcoxon signed-rank tests. Multiple comparisons were controlled with Benjamini-Hochberg FDR, and a second-level FDR was applied across frequency bands where relevant. Note: Granger causality here refers to statistical predictability of one region's future activity from another region's past activity, conditional on remaining regions.

Subjective VAS scores increased from placebo to LSD: mean changes (± SD) were 10.4 ± 4.8 for Emotional Arousal, 6.7 ± 6.0 for Positive Mood and 5.7 ± 7.2 for Ego Dissolution. In the fMRI Delta analysis (LSD versus placebo), the combined bilateral DLPFC seed showed increased connectivity with canonical Default Mode Network hubs, namely medial prefrontal cortex and posterior cingulate cortex, and decreased connectivity with several cortical regions including left angular gyrus, right supramarginal gyrus, left precuneus and a left DLPFC region. Analysed separately, the left DLPFC seed exhibited a significant reduction in RSFC with sensorimotor cortex under LSD, whereas the right DLPFC seed showed no significant Delta effects. In the covariate analyses linking RSFC to subjective experience, ego dissolution correlated positively with combined DLPFC connectivity to two clusters peaking in the left thalamus and right fusiform gyrus (rFG). A confirmational reverse analysis seeded with these clusters returned outputs that included a right DLPFC cluster and the right inferior frontal gyrus (rIFG); scatter plots reported by the authors showed stronger correlations in the confirmational analysis, indicating specificity of that rDLPFC cluster for ego dissolution. Emotional arousal correlated significantly with increased connectivity between the rDLPFC and the intraparietal sulcus (IPS); the reverse analysis reproduced part of the rDLPFC cluster and additionally revealed regions in bilateral anterior insulae, dorsal anterior cingulate cortex and middle temporal gyrus—nodes of the Salience Network (SN). No significant correlations were found between positive mood and connectivity of the left, right or combined DLPFC. Exploratory ASC correlations (reported before FDR correction) included reduced RSFC between the lDLPFC and left lingual gyrus correlating with anxiety, and increased RSFC between the rDLPFC and left putamen correlating with Changed Meaning of Percepts. MEG Granger causality analyses found that, within each of the four fMRI-defined networks, pairwise-conditional time-domain GC values were significant under both placebo and LSD (p < 0.002). Between placebo and LSD, no significant differences emerged in time-domain GC. Frequency-domain GC did show selective between-condition changes: LSD increased theta-band GC from the thalamus to the rDLPFC (p = 0.0366) and increased beta-band GC from the IFG to the rDLPFC (p = 0.0366) in the ego reverse network. There were no significant between-condition frequency-domain differences for the ego forward, emotional forward, or emotional reverse networks. The authors note that band-limited GC values summed to corresponding time-domain GC as a consistency check.

Coleman and colleagues interpret their multimodal findings as evidence that the DLPFC, and particularly the right DLPFC, is involved in LSD-induced ego dissolution and emotional arousal, with some hemispheric lateralisation. The fMRI analyses showed that ego dissolution relates to increased connectivity between a combined DLPFC seed and the thalamus and fusiform gyrus, and that a confirmational reverse analysis localises this network to a right DLPFC subregion and the rIFG. Emotional arousal correlated with connectivity between the rDLPFC and IPS and, in the reverse analysis, additionally implicated salience-network hubs (bilateral anterior insulae and dACC). These patterns are interpreted in light of TMS literature suggesting left/right DLPFC functional differences and theories linking salience processing to emotional arousal. Directed-connectivity results from MEG further shaped the authors' account of mechanism: LSD increased theta-band information flow from the medial dorsal thalamus to the rDLPFC and beta-band flow from the IFG to the rDLPFC within the ego reverse network. The authors propose that elevated bottom-up thalamocortical signalling may reflect disrupted thalamic gating, producing a sensory or representational "overload" that contributes to the phenomenology of ego dissolution. They connect this to models such as REBUS (relaxed priors) in which psychedelics reduce top-down constraints on perception and belief, and suggest that increased IFG→rDLPFC beta-band flow may index attempts by prefrontal systems to integrate disconfirmatory evidence when priors are loosened. The investigators also situate their findings relative to psychosis research: some directed-connectivity signatures resemble those reported in schizophrenia, particularly altered thalamus–prefrontal interactions, but they emphasise important differences in chronicity and phenomenology between psychedelic states and clinical psychoses. The discussion recognises key limitations reported by the authors: a modest analysed sample size (n = 15), potential confounding by pharmacological vascular effects on the fMRI BOLD signal (mitigated in part by concordant MEG results), a possibly insufficient 14-day washout between sessions given reported longer-term brain effects of LSD, and the inherent interpretive limits of resting-state data for mapping specific psychological processes. The authors additionally note that MEG source localisation to subcortical structures such as the thalamus is challenging and that directed-connectivity estimates from MEG were not directly correlated with ego-dissolution VAS scores because those ratings were incomplete for some MEG-included participants. They propose that dynamic causal modelling of fMRI data or task-based paradigms probing self-related cognition could help strengthen mechanistic inference. Overall, the authors suggest their convergent fMRI and MEG results support a model in which altered DLPFC connectivity—particularly increased bottom-up thalamocortical signalling to a right prefrontal locus—contributes to the experiences of ego dissolution and heightened emotional arousal under LSD, and that parsing left versus right DLPFC function may be informative for both psychedelic mechanisms and psychiatric interventions.

The study concludes that changes in functional connectivity of the DLPFC relate to subjective effects of the LSD-induced psychedelic state. Emotional arousal correlated with connectivity between the salience network and IPS and with the right but not left DLPFC, supporting a lateralisation of DLPFC function. Ego dissolution was associated with increased connectivity between the combined DLPFC and clusters in the thalamus and fusiform gyrus. Granger-causality analysis of MEG data indicated elevated theta-band directed flow from the thalamus to the rDLPFC, consistent with increased bottom-up information flow and a flattening of hierarchical control under LSD. The authors highlight the value of distinguishing left and right DLPFC, considering DLPFC heterogeneity and receptor architecture, and combining fMRI and MEG to probe the neural mechanisms of psychedelic experience. They propose that the networks identified here may be relevant to understanding both altered states of consciousness and certain features of psychiatric disorders, and that ego dissolution may contribute to therapeutic effects by transiently relaxing self-related beliefs.